Acupuncture stimulation improves scopolamine-induced ... Acupuncture stimulation improves scopolamine-induced

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  • Lee et al. BMC Complementary and Alternative Medicine 2014, 14:338http://www.biomedcentral.com/1472-6882/14/338

    RESEARCH ARTICLE Open Access

    Acupuncture stimulation improvesscopolamine-induced cognitive impairment viaactivation of cholinergic system and regulationof BDNF and CREB expressions in ratsBombi Lee1*, Bongjun Sur1, Jaegul Shim1, Dae-Hyun Hahm1,2 and Hyejung Lee1,2*

    Abstract

    Background: Acupuncture is an alternative therapy that is widely used to treat various neurodegenerative diseasesand effectively improve cognitive and memory impairment. The aim of this study was to examine whetheracupuncture stimulation at the Baihui (GV20) acupoint improves memory defects caused by scopolamine (SCO)administration in rats. We also investigated the effects of acupuncture stimulation at GV20 on the cholinergicsystem as well as the expression of brain-derived neurotrophic factor (BDNF) and cAMP-response element-bindingprotein (CREB) in the hippocampus.

    Methods: SCO (2 mg/kg, i.p.) was administered to male rats once daily for 14 days. Acupuncture stimulation atGV20 was performed for 5 min before SCO injection. After inducing cognitive impairment via SCO administration,we conducted a passive avoidance test (PAT) and the Morris water maze (MWM) test to assess behavior.

    Results: Acupuncture stimulation at GV20 improved memory impairment as measured by the PAT and reduced theescape latency for finding the platform in the MWM test. Acupuncture stimulation at GV20 significantly alleviatedmemory-associated decreases in the levels of choline acetyltransferase (ChAT), BDNF and CREB proteins in thehippocampus. Additionally, acupuncture stimulation at GV20 significantly restored the expression of cholinetransporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), BDNF and CREB mRNA in the hippocampus.These results demonstrate that acupuncture stimulation at GV20 exerts significant neuroprotective effects againstSCO-induced neuronal impairment and memory dysfunction in rats.

    Conclusions: These findings suggest that acupuncture stimulation at GV20 might be useful in variousneurodegenerative diseases to improve cognitive functioning via stimulating cholinergic enzyme activities andregulating BDNF and CREB expression in the brain.

    Keywords: Scopolamine, Memory, Cholinergic neurons, Brain-derived neurotrophic factor, cAMP-responseelement-binding protein

    * Correspondence: bombi@khu.ac.kr; hjlee@khu.ac.kr1Acupuncture and Meridian Science Research Center, College of KoreanMedicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul130-701, Republic of Korea2BK21 PLUS Korean Medicine Science Center, College of Korean Medicine,Kyung Hee University, Seoul 130-701, Korea

    2014 Lee et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

    mailto:bombi@khu.ac.krmailto:hjlee@khu.ac.krhttp://creativecommons.org/licenses/by/4.0http://creativecommons.org/publicdomain/zero/1.0/

  • Lee et al. BMC Complementary and Alternative Medicine 2014, 14:338 Page 2 of 14http://www.biomedcentral.com/1472-6882/14/338

    BackgroundAlzheimers disease (AD) is a progressive neurodegenerativedisorder of the brain that is characterized by deteriorationof memory and cognitive function due to cholinergicnervous system dysfunction [1]. Decreased cholinergicfunction in the brain, as primarily observed in patients withAD, can result in a decline in memory and cognitivefunction [2]. Accordingly, various cholinergic drugs havebeen approved to treat or alleviate AD, and they exert theirtherapeutic effects by counteracting acetylcholine (ACh)deficits and consequently enhancing ACh levels in thebrain [3]. In fact, the most common therapy for ADis administration of acetylcholinesterase (AChE) inhibitors,such as donepezil, galantamine, and rivastigmine, whichtemporarily increase the availability of ACh at cholinergicsynapses [4]. Nevertheless, new drugs used to treatAD patients are limited due to their short half-livesand excessive side effects caused by peripheral cholinergicsystem activation and hepatotoxicity, the most frequent andcritical side-effect of these drugs [5]. Thus, an alternativetreatment modality for AD patients is required.Scopolamine (SCO) is a tropane alkaloid drug that

    exhibits competitive antagonism at muscarinic acetylcholinereceptors (mAChRs) by interfering with cholinergictransmission in the central nervous system CNS; [6].Therefore, SCO administration to animals is used asan experimental model of the cognitive deteriorationand memory disturbances in AD; this animal model isfrequently used to screen for drugs that have potentialtherapeutic value in AD-type dementia patients [7-9]. SCOadministration not only induces dysregulation of thecholinergic neuronal pathway and memory circuits inthe CNS but also reduces the expression of brain-derivedneurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) in the brain; thus, BDNF and CREBmay act a novel therapeutics to treat hippocampal dysfunc-tion and memory deficits [10,11]. BDNF is believed to beresponsible for synaptic plasticity and memory perform-ance, particularly in the water maze test, and is coupled toCREB activation [12,13]. Several studies demonstrated thathippocampal BDNF and CREB are important in long-termmemory formation [14], and play important roles in patho-logical conditions and neurodegenerative diseases such asAD [15,16].In East Asian nations, acupuncture is used widely to

    treat many neurodegenerative disorders, including AD,Parkinsons disease (PD) and dementia [17]. Its therapeuticeffects and mechanism of action have been investigated inboth clinical and animal studies. This alternative therapy isknown to modulate biochemical balance in the CNS and tomaintain homeostasis [18]. Specifically, Baihui (GV20) isone of the most important acupoints targeted to alleviateneurodegenerative disorders and cognitive impairment inacupuncture treatment [19]. Several studies showed that

    acupuncture stimulation at GV20 reduces cerebral infarctand increases dopamine levels in the brain tissue ofischemia-reperfusion injured rats [20], and reduces theamount of apoptotic neurons in the hippocampal CA1 areaof rats with vascular dementia [19]. Although a brief reportof the anti-dementia or anti-ischemic activity of GV20acupuncture stimulation has been published, whetherGV20 acupuncture stimulation therapeutic efficacy inalleviating spatial cognitive function following repeatedSCO-induced neuronal impairment is due to cholinergicsystem regulation or BDNF and CREB expression remainsunknown [21]. Indeed, one study failed to demonstrate atherapeutic effect of acupuncture on AD [22]. Such majordifferences could be attributable to differences in acupunc-ture stimulation parameters, as selection of appropriatestimulation parameters is a crucial factor in the efficacy ofacupuncture [23]. Therefore, it is appropriate to investigatechanges in spatial cognitive function and neuronalbiomarkers in SCO-treated cognitive impairment tobetter understand the therapeutic effects and mechanismsof action of acupuncture stimulation at GV20.The aim of the present study was to evaluate the ability

    of acupuncture stimulation at GV20 to improve learningand memory in rats exposed to repeated SCO-inducedmemory deficits as measured by their performance in thepassive avoidance test (PAT) and the Morris water maze(MWM) test. We also investigated how these activities wererelated to the cholinergic system and the expression ofCREB and BDNF in the CNS, and whether acupuncturestimulation exerted anti-AD activity in this model to eluci-date neural mechanisms underlying the memory-enhancingeffect of acupuncture stimulation.

    MethodsAnimalsAdult male SpragueDawley (SD) rats weighing 220240 g were obtained from Samtako Animal Co. (Seoul,Korea). The rats were housed in a limited-access rodentfacility with up to five rats per polycarbonate cage. Theroom controls were set to maintain the temperatureat 22 2C and the relative humidity at 55 15%. Cages werelit by artificial light for 12 h each day. Sterilized drinkingwater and standard chow diet were supplied ad libitum toeach cage during the experiments. The animal experimentswere conducted in accordance with the National Institutes ofHealth Guide for the Care and Use of Laboratory Animals(NIH Publications No. 8023), revised in 1996, and wereapproved by the Kyung Hee University Institutional AnimalCare and Use Committee. All animal experiments began atleast 7 days after the animals arrived.

    Experimental groupsIn order to develop learning and memory deficits in thebrain, the rats were intraperitoneally injected with 2 mg/kg

  • Lee et al. BMC Complementary and Alternative Medicine 2014, 14:338 Page 3 of 14http://www.biomedcentral.com/1472-6882/14/338

    SCO, dissolved in physiological saline, once a day for14 days. Normal animals received saline instead of SCO asa vehicle control. Different rats in an experimentalgroup were subjected to either behavioral testing orimmunohistochemistry. The rats were randomly dividedinto five groups of six or seven individuals as follows:normal group (SAL group, n = 7), the SCO-induced andsaline-treated group (SCO group as a control, n = 7), theSCO-induced and Baihui (GV20) acupoint-stimulatedgroup (SCO +GV20 group, n = 7), the SCO-induced andYangji (TE4) acupoint-stimulated group (SCO+TH4group, n = 6), and SCO-induced and non-acupoint (onthe tail)-stimulated group (SCO+TA g